Bovine immunodeficiency-like virus (BIV) is a recently characterized lentivirus isolated from cattle. It is the only lentivirus which has been isolated from cattle and has structural, genetic, antigenic as well as biological similarity to the human immunodeficiency virus (HIV). Infected animals developed lymphoproliferative disorders, lymphadenopathy, lymphocytosis, lymphomas, central nervous system disorders and emaciation. It has been estimated that BIV infection may be common in cattle and as much as 4% of cattle in certain areas may be infected with BIV. It was demonstrated in human lentivirus HIV that exogenous infections by other human viruses, like herpes, could play an important role in the pathogenesis of AIDS. Cattle are often infected with viruses, such as bovine herpes-1 and bovine viral diarrhea virus. These viruses are ubiquitous in nature, cause respiratory and genital infections, and have important economic impacts in the cattle industry. An annual loss of 500 million to 1 billion dollars is due to diseases caused by these viruses. Our overall objective of this proposed project is to understand the biology of BIV infection and its interactions with other viruses in causing diseases. We have obtained preliminary evidence that BIV can be activated by bovine herpesvirus-1 Cooper strain (BHV-1). It is of paramount importance to determine if BIV plays a role in the pathogenesis of herpes infection and vice versa. Since both viruses are cytolytic, enhancement of virus production by each other may play an important role in bovine disease. Our immediate approaches and specific aims are: 1) to study the interactions between BHV-1 and BIV in vitro, to identify and characterize the BHV-1 viral genes that may be involved in the transactivation; 2) to study whether there is a bi-directional interaction between BIV and BHV-1; 3) to study the interaction between BIV and other strains of BHV-1, such as the encephalitic BHV-1 strain; 4) to conduct a pilot animal infectivity study in order to understand the roles played by the interacting viruses in pathogenesis. Our in vitro approach is to infect cells with both viruses and then measure the level of viral production. In addition, we propose to study the mechanism of transactivation and to identify the herpesvirus gene(s) that is responsible for the transactivation of BIV. Our animal studies will involved challenging the animals with both viruses, the pathogenesis and the disease course of superinfected animals will be compared to those that are only infected by a single virus. Various immunological and clinical assays will be used to follow infection, such as viral isolation, antibody titer, T cell proliferative response and T4/T8 cell ratio. Pathological analyses will also be performed on these animals at the end of the study. The studies proposed here are significant as they will generate valuable information about diseases that may be associated with BIV infection, and to understand its interaction with the host and with other viruses. It can then further be used as a model for studying animal lentivirus infection, its mechanism in immunosuppression, tumor formation and as a system for testing possible lentiviral vaccines.